The conversion of chemical waste streams into valuable complex molecules is a grand challenge in chemical synthesis. One of the most underutilized waste streams is fluoroform (HCF3), a potent greenhouse gas and a byproduct of the Teflon industry. Although this gas contains the trifluoromethyl functional group (CF3), whose extreme lipophilicity and resistance to degradation makes it indispensable in medicinal chemistry, it is currently incinerated rather than used as a CF3 feedstock because of its strong C—H bond and unstable CF3− anion. Additionally, current methods for installing the CF3 group in organic molecules generate substantial waste byproducts, present significant operational challenges, and are cost-prohibitive in large-scale applications. For these reasons, a longstanding goal in synthetic chemistry has been the development of new trifluoromethylation reagents with: (1) economic preparation at ambient temperature from HCF3, (2) very high inherent reactivity, and (3) minimal waste generation. Disclosed herein is a CF3− transfer reagent satisfying these criteria, developed through the application of a new conceptual framework. The prior state of the art for the transformation of HCF3 into useful trifluoromethylation reagents required the use of expensive bulky bases and strong Lewis acids (LA). These reagents must be irreversibly activated prior to CF3− transfer, resulting in destruction of the Lewis acid and generation of stoichiometric waste. It is shown that a highly reactive CF3− adduct can be synthesized from alkali metal hydride, HCF3, and borazine Lewis acids in quantitative yield at room temperature. The reagents possess Grignard-like nucleophilicity and thermal stability without additional chemical activation, and after CF3− transfer the free borazine is quantitatively regenerated. These features expand the scope of nucleophilic trifluoromethylation to new classes of substrates and enable rapid (<30 minute) synthesis of popular nucleophilic, radical, and electrophilic trifluoromethylation reagents with complete recycling of the borazine Lewis acid.
The trifluoromethyl functional group is widely used in medicinal chemistry to enhance the bioavailability, lipophilicity, and resistance to oxidative degradation of drug molecules. However, the trifluoromethylation of complex organic compounds is difficult because of the instability of isolated CF3 fragments, generally low reactivity of CF3 ligands in organometallic cross-coupling, and the absence of any synthetic biology approaches for its incorporation. Unlike other alkyl groups, which can be readily transferred to electrophilic substrates using robust organolithium and Grignard reagents, analogous LiCF3 and MgCF3 reagents are not stable because they irreversibly eliminate fluoride at −80° C. However, CF3− can be stabilized through the formation of a Lewis acid (LA)-CF3 adduct; this strategy forms the basis of all popularly used nucleophilic, radical, and electrophilic trifluoromethylation reagents.
Unfortunately, CF3− reagents stabilized by strong Lewis acids lack the synthetic versatility, economic preparation, and atom efficiency needed for large-scale use. Strong LA-CF3 adducts such as SiMe3CF3 possess little inherent reactivity and must be irreversibly activated with exogenous nucleophiles (e.g. F—) to effect CF3 transfer, resulting in stoichiometric waste byproducts. Despite twenty years of optimization, the cost of common LA-CF3 reagents still limits their use in large-scale processes.
Fluoroform (HCF3), a byproduct of Teflon manufacturing (<$0.10/mole), is an attractive alternative starting material for preparing CF3 transfer reagents. If HCF3 and recyclable Lewis acids could be used to generate LA-CF3 reagents in economically efficient, single-step reactions that generate minimal waste, it may dramatically lower the cost of synthesizing trifluoromethylated drug compounds. In addition to simultaneously reducing the cost of the trifluoromethyl group in large-scale processes and putting a greenhouse gas to productive use, this strategy could also present opportunities for expanding the scope of trifluoromethylation reactions.
The trifluoromethyl functional group is ubiquitous in drugs and fine chemicals. The unstable anion CF3— is a common intermediate in nucleophilic trifluoromethylation reactions, and its stabilization by strong silane Lewis acids has enabled the design of successful CF3— reagents. However, these reagents remain expensive because their synthesis from cheap HCF3 has demanded strong, bulky amide or phosphazene bases capable of both deprotonating HCF3 and avoiding adduct formation with the strong Lewis acids needed to stabilize the CF3− anion. Additionally, their use generates unavoidable silicon-containing waste products because the release of reactive CF3− is triggered by the irreversible formation of a strong Si—O or Si—F bond. If reactive and recyclable CF3− reagents could be synthesized using low-cost HCF3 and simple alkoxide or hydride bases, it could lead to a significant reduction in the cost of installing the trifluoromethyl group. It is shown herein that a highly reactive, but stable, CF3− adduct can be synthesized from potassium toluide or sodium/potassium hydride, HCF3, and the weak Lewis acid borazine in >95% yield at room temperature. It is a powerful nucleophilic reagent with reactivity strongly resembling a Grignard reagent, allowing it to trifluoromethylate a wide variety of polar unsaturated bonds in organic compounds, electron-deficient aromatic halides and pseudohalides, and diverse transition metal and main group element substrates with complete regeneration of the free borazine Lewis acid. Among the trifluoromethylation products are the principal reagents used for the four major classes of direct trifluoromethylation reactions: trifluoromethyl trimethylsilane (CF3 anion source), KSO2CF3 (CF3 radical source), Togni I (CF3 cation source), and CuCF3 (cross coupling reagent). Through sequential reagent addition, borazine can be used as a recyclable Lewis acid catalyst. One borazine Lewis acid can be prepared on a kilogram scale from ethanolamine and boric acid and hydrolyzes in water to non-toxic substances, enabling large-scale applications. Using the disclosed methodology, it is now possible to trifluoromethylate diverse substrates using fluoroform and inexpensive bases, enabling a large reduction in the cost of installing the trifluoromethyl group in industrial and laboratory settings. The disclosed strategy of using a fine-tuned borazine Lewis acid to stabilize the trifluoromethyl anion can be applicable to the stabilization of other unstable anions generated using inexpensive bases, and that the stability of the borazine ring to decomposition will enable diverse catalytic applications.
The inert industrial waste gas fluoroform (HCF3) is the most inexpensive source of the medicinally valuable trifluoromethyl functional group, but its weak acidity, strong C—H bond, and unstable CF3− anion have prevented practical applications of this reagent from becoming a reality. Of these troublesome properties, the most problematic is the instability of CF3− to fluoride elimination, occurring at temperatures as low as −80° C. While certain favorable organic substrates can still be trifluoromethylated in modest yield at such low temperatures, the CF3− anion has required stabilization by a strong Lewis acid to enable practical applications beyond the alkylation of simple ketones and aldehydes. Such Lewis-stabilized CF3— adducts have become ubiquitous trifluoromethylation reagents in recent years, providing ready access to nucleophilic, radical, and electrophilic trifluoromethylation reactivity. Despite their popularity, they remain expensive because of the two key dilemmas preventing their economic synthesis from HCF3: the strong base needed to deprotonate HCF3 (pka >28 in DMSO) must be compatible with the strong Lewis acids used to stabilize CF3−, and the Lewis acid itself must not first abstract a fluoride ion from CF3−.
To address these dilemmas, expensive, bulky bases such as KHMDS (pKa=30) and P4-tBu (pKa=40) along with low temperatures (−80° C.) have been used to activate HCF3 and generate stable Lewis acid adducts, but only SiR3CF3 (80%), KBF3CF3 (53%), and KSO3CF3 (18%) can be made with this methodology. The only example of HCF3 derived CF3— metal complexes using inexpensive bases is Grushin's “CuCF3” solution, which requires excess base, the toxic solvent DMF, and treatment with hydrofluoric acid. Three other metal complexes can be synthesized through stoichiometric reactions with HCF3, but are impractically expensive: Zn(CF3)2 can be prepared from Zn(TMP)2, Pd(dppp)PhCF3 from the metal hydroxide, and highly unstable Ir(PCP)(H)(CF3) through oxidative addition to the C—H bond; catalytic reactions with these four compounds have not been reported. These strategies have significantly advanced HCF3 activation chemistry and reduced reliance on syntheses using ozone-depleting CF3I to generate CF3− reagents such as SiMe3CF3, but the high expense of the required bases, unwanted waste from strong Lewis acids, stoichiometric metals/salts, low temperatures, and low generality have combined to prevent significant reductions in the cost of organic and inorganic trifluoromethylation reactions.
In contrast with current strategies, which employ strong ionic Lewis acids such as TMSCl to stabilize CF3−, described herein are design neutral, weak Lewis acids that could avoid irreversible reactions with inexpensive, sterically unhindered bases while still providing optimal stabilization to HCF3 derived CF3−. Importantly, it is hypothesized that a precisely tuned Lewis acidity could provide sufficient stability to CF3− to prevent fluoride elimination while still providing high CF3− nucleophilicity. These optimized reagents offer the potential for room temperature HCF3 activation, regeneration of the free Lewis acid after high-yielding CF3− transfer, and tolerance of cheap, unhindered strong bases, providing superior reactivity and economy while minimizing waste.